Atherosclerotic stenosis of the major intracranial arteries is an important cause of stroke, accounting for approximately 50,000 strokes per year in the USA at an annual cost of $750,000,000 in the first year after the stroke, and increasing to $4.5 billion over the life time of these patients. Atherosclerosis is attributable to three main pathological processes: endothelial dysfunction, vascular inflammation, and infiltration of the vascular wall by bioactive lipids. It is unknown, however, whether biomarkers that reflect these processes are relevant in patients with intracranial atherosclerosis. To address this question, we propose to study the relationship between promising biomarkers of atherosclerosis and risk of major vascular events in patients with symptomatic intracranial stenosis. This research proposal builds on the existing infrastructure and close collaboration with the recently funded NINDS sponsored trial - Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS - M.Chimowitz, PI) - the first randomized, multi-center Phase III clinical trial designed to evaluate the safety and efficacy of intracranial angioplasty and stenting in patients with symptomatic intracranial atherosclerosis. The Primary Aim of the current proposal is to determine whether serum biomarkers of inflammation in patients with symptomatic intracranial stenosis are independent predictors of recurrent stroke. We hypothesize that elevated levels of inflammatory biomarkers (hsCRP, PAI-1 and E-selectin), measured at the time of enrollment in SAMMPRIS, are associated with an increased risk of the primary endpoint, defined as recurrent stroke in the territory of the symptomatic stenotic artery. Our Exploratory Aim will be to determine whether the number of circulating endothelial progenitor cells (a marker for vascular repair) is an independent predictor of recurrent stroke in the territory of the symptomatic stenotic artery. For the exploratory aim, we will test the hypothesis that decreased levels of circulating endothelial progenitor cells are associated with an increased risk of the primary endpoint. Additional exploratory analyses will include a comparison of the efficacy of intensive medical therapy combined with angioplasty and stenting to intensive medical therapy alone in reducing major vascular events among patient groups with and without elevated levels of biomarkers. For the primary aim in this proposal, the sample size determined for SAMMPRIS (n = 764) provides 80% power to find a statistically significant result if the true hazard ratio for any of the 3 biomarkers is, at a minimum, in the range of 1.8 to 2.0 (after adjusting for multiple comparisons). It is expected that the results of this study will provide unique and novel data on the relationship of atherosclerotic biomarkers with outcome in patients with symptomatic intracranial stenosis. Refining risk assessment in patients with intracranial atherosclerosis could lead to a more tailored approach to treatment as well as a better understanding of the pathological processes involved in this common and understudied disease.